Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of inflammatory disease. Their anti-inflammatory effects are believed to result from their ability to inhibit the formation of prostaglandins by prostaglandin H synthase (COX). Two isoforms of prostaglandin H synthase, COX-1 and COX-2 have been identified. COX-1 is constitutively expressed in many tissues, while the expression of COX-2 is regulated by mitogens, tumor promoters, and growth factors. High expression of COX-2 has been reported in human colorectal tumors and tumors from other tissues, suggesting a role for this enzyme in regulating tumor growth. NSAIDs are effective in reducing human and rodent colorectal, and possibly, breast and lung cancer. In addition, retrospective and prospective studies link NSAID usage to a reduced risk for colorectal cancer death. NSAIDs are effective in reducing the number and size of polyps in animal models, and epidemiological studies indicate that use of NSAIDs provide a 40–50% reduction in mortality from colorectal cancer.
Our understanding of the mechanisms by which NSAIDs exert their anti-tumor effect is not clear. One possible mechanism is altered arachidonic acid (AA) metabolism, since NSAIDs inhibit the formation of prostaglandins by COX-1 and COX-2. Recent data suggest that inhibition of COX by NSAIDs may increase the cellular pool of AA, resulting in the hydrolysis of sphingomyelin to ceramide, which promotes apoptosis. Some data link NSAID chemoprevention in colorectal cancer cells to prevention of angiogenesis and induction of apoptosis. COX appears to regulate angiogenesis induced by colon cancer cells and NSAIDs appear to limit tumor growth. In epithelial cells of the intestinal crypt, elevated COX-2 expression appears to attenuate apoptosis. Some evidence links NSAID-induced apoptosis to inhibition of COX, but other data suggest a prostaglandin-independent mechanism for the induction of apoptosis. PPARγ agonists also have anti-tumorigenic activity and stimulate apoptosis. For example, ligand activation of PPARγ inhibits proliferation of breast cancer cells, and the addition of PPARγ ligands to cancer cells induces apoptosis. PPARγ agonists also inhibit the growth of transplantable tumors in a nude mouse model.
As is evident from the foregoing, NSAIDs, and the pathways they activate, have great potential for use in the war against cancer. However, as is also evident from the above, insufficient information has been available regarding the NSAID-induced or associated anti-cancer pathways, to help identify agents that are potentially advantageous as cancer treatments. What is needed are novel reagents and methods that can be used to screen for compounds that show promise as anti-cancer agents.